Modafinil as a means to reduce tobacco use and abuse

Modafinil, first developed in France at Lafon Laboratories by Michel Jouvet, has become a recognized treatment for narcolepsy and sleep disorders, ranging from sleep apnea to shift work sleep disorder. It is touted for its ability to promote wakefulness by suppressing the desire or reducing the perceived need for sleep. While the exact mechanisms by which modafinil exerts its effects remain unclear, we are most interested in its ability to increase the presence of monoamine neurotransmitters, such as dopamine, in synapses by binding to reuptake sites and blocking these neurotransmitter transporters, while also inhibiting many subsequent transporter actions. This has been suggested as a possible reason for its wakefulness-promoting capabilities and its low abuse potential (though it’s worth noting that some users report mild euphoria upon first use, with varying success in replicating this feeling). Although nicotine itself has a “relatively weak” addictive potential, tobacco smoke has been shown to inhibit monoamine oxidases (MAOs) in a way that significantly enhances nicotine’s addictive potential. Additionally, nicotine’s effects on wakefulness, sleep, and appetite—factors mitigated by modafinil—may involve overlapping or related physiological processes.

Introduction

Modafinil is a relatively new drug, most commonly prescribed for treating sleep disorders and controlling wakefulness in otherwise healthy patients. Its mechanisms of action and precise physiology behind its profound effects are not fully understood and require further study. We aim to provide evidence, primarily through analysis of its core physiological effects, suggesting its potential use as an aid for smokers attempting to abstain or quit smoking by avoiding nicotine.

Few studies have been published on the specific topic of modafinil’s effects in treating nicotine dependence, but two small-scale studies with conflicting results provide grounds for expanding research into this potential treatment. Presented in order of publication, the first study involved 19 smokers and examined those given modafinil orally, followed by nicotine lozenges after 2 hours and 10 minutes. Subjects were tested on various self-reported characteristics, with reports indicating an increase in the “drug strength” of the lozenges for those taking modafinil, but the study noted that modafinil had no effect on nicotine withdrawal symptoms. (30)

The second study, conducted on an even smaller group of just 9 subjects, reached somewhat contradictory conclusions compared to the previous study. Its findings suggest that combining modafinil with nicotine replacement therapy as an aid for smoking cessation has benefits in alleviating withdrawal symptoms. (31) It would be effective to investigate modafinil’s impact on smoking cessation in controlled laboratory settings and over multiple sessions to more accurately mimic its use in patients already prescribed the drug, as well as the reality of a smoker’s journey toward permanently eliminating tobacco use.

Clinical Use of Modafinil

Modafinil is a wakefulness-promoting agent, best known for alleviating symptoms of sleep deprivation or excessive sleepiness in a manner distinctly different from classic amphetamines, as it does not stimulate but rather mitigates sleep. (29) Modafinil has been confidently prescribed for treating sleep disorders such as narcolepsy, sleep apnea, and shift work sleep disorder, as well as attention or learning disorders like ADHD. Additionally, it has shown promise in treating depressive symptoms of bipolar disorder in a study excluding patients with stimulant-induced mania; a single dose can accelerate recovery from general anesthesia post-surgery; a single dose helped night-shift workers attend a daytime lecture after work but did not improve their driving ability and subsequently caused sleep disturbances. (29) Modafinil’s effects on excessive sleepiness due to Parkinson’s disease, cognitive functions in chronic fatigue, and cocaine dependence have been studied with mixed results; all these trials were conducted on small samples. No cases of habituation or dependence have been documented, though there may be some potential for abuse. (29)

Psychomimetic Effects of Modafinil

Modafinil users most commonly report feelings of heightened wakefulness and normalcy, as well as improved focus and other cognitive benefits. (16) It is most effective in treating episodes of excessive daytime sleepiness, with users reporting feelings of relief and enhanced overall well-being.

Effects typically manifest within 1-2 hours and often last 5-8 hours for frequent users, while infrequent users report effects lasting up to 10-15 hours after ingestion (orally).

There have been conflicting reports about users developing tolerance, but scientific evidence generally does not support this claim. It would be prudent to consider, at least, the idea that the drug loses some psychological intensity in its effects after prolonged use, as users may feel the effect diminishes over time as their body becomes accustomed to the chemical. (18) Interestingly, anecdotal evidence suggests there is little proof that modafinil leads to dependence or physical addiction beyond tolerance formation. Users do not appear to fall below their baseline abilities upon discontinuation after prolonged use, unlike other psychostimulants such as caffeine or amphetamines. (17) Nonetheless, the potential for modafinil abuse should be considered in the context of psychological dependence, as users often feel that returning to baseline performance puts them at an unacceptably disadvantaged state compared to their chemically enhanced selves.

Psychotomimetic Effects of Tobacco

The physical effects most commonly associated with tobacco use or nicotine exposure are stimulation and sedation, with the former more prevalent at low doses and the latter at high doses. This contradiction is termed Nesbitt’s paradox, as Nesbitt observed that smokers behave more relaxed as their smoking-induced arousal increases, yet abnormal heartbeats and dizziness may occur. (20)

Cognitive effects of nicotine use include accelerated thinking; improved attention, memory, and motivation; euphoria, sexual arousal, and compulsive redosing; anxiety and anxiety suppression, with the relationship between the latter pair mirroring Nesbitt’s paradox, where anxiety arises as a response to the stimulating effects of low nicotine doses, while anxiety suppression results from sedative effects at higher doses. Beta-endorphins are released at high doses. (20)

Mechanism of Action

Orexins/Hypocretins

Orexins, or hypocretins, are neuropeptides that regulate arousal, wakefulness, and appetite. They play a key role in understanding the underlying mechanisms of narcolepsy and other sleep disorders treated with modafinil. Mice with orexin gene knockouts typically exhibit signs of narcolepsy or excessive, uncontrollable daytime sleepiness. (1) Additionally, central administration of orexins promotes wakefulness and is considered functionally significant for regulating energy expenditure, as it is linked to managing sleepiness symptoms. Further evidence for orexins’ role in sleep management comes from studies showing that monkeys deprived of sleep for 30-36 hours and injected with orexins exhibit reduced motivation to sleep and even decreased overall fatigue. (2)

As orexin-A receptors are considered critical for motivation in drug-seeking behavior, a study investigated their impact on curbing nicotine-related addictive behavior in rats given a selective orexin-A antagonist. Self-administration of nicotine and motivation to seek and obtain the drug decreased. The insular cortex, involved in regulating craving, contains orexin-A receptors; smokers with insular cortex damage have been reported to lose the desire to smoke. (3)

Nicotine increases orexin and its receptor expression in various brain regions. (5) Modafinil has been shown to be more effective in promoting wakefulness in rats genetically modified to have a non-functional orexin system compared to wild-type rats, which was linked to compensatory facilitation of central arousal through non-orexin-based systems. In these null mice, the orexin system appears to mediate some of the drug’s wakefulness-promoting effects. (6)

Regarding the orexin system, it may be that modafinil’s stimulation of orexin presence in the brain creates an environment similar to that immediately following a preferred nicotine dose, during which the user is likely in a refractory period, less responsive to the drug’s desired effects and less inclined to redose. By saturating the brain with chemicals the user typically associates with satisfaction from nicotine consumption, the orexin system may regulate additional self-administration of nicotine, reducing use during modafinil’s active period. (4)

Histamine

The histamine H1 receptor is involved in modulating the sleep-wake cycle, nociception, appetite regulation, and cognitive functions. Additionally, the histamine H3 receptor modulates nociception and food intake, among other functions. (8) Modafinil has been shown to increase histamine production by 150% above baseline release. Intravenous modafinil injection also led to a similar increase in histamine production, but notably, this increase was not observed when injected directly into the tuberomammillary nucleus, an area associated with arousal, learning, memory, and sleep, where histaminergic neurons are primarily located. (9)

Nicotine appears to have an antagonistic relationship with histamine at high doses. At low doses, nicotine seems to have a residual inhibitory effect on histamine. This latter effect is attributed to insensitivity caused by nicotine-induced paralysis of ganglionic cells mediating histamine release, combined with post-effects of gut contraction or acetylcholine release leading to contraction. (7)

Dopamine

The mesocorticolimbic dopaminergic (DA) system comprises a series of projections originating in the ventral tegmental area (VTA) and innervating the striatum, amygdala, and prefrontal cortex, which are heavily involved in motivation for addictive behavior and drug-related learning, such as with nicotine, cocaine, and amphetamines. Increased available DA in mesocorticolimbic systems, such as the nucleus accumbens, has long been associated with positive reinforcement of these drugs, leading to their high abuse potential and possible dependence. (11)

Evidence suggests that DA signals novelty and reward prediction errors, as DA neuron activation reflects the difference between expected and actual rewards. This inhibition of prior experience by presenting stimuli creates a complex learning environment. (13) The mesocorticolimbic system generally integrates knowledge from past interactions with salient environmental information. (12) The DA system provides a context in which an animal or human can respond to potentially rewarding stimuli, such as food or sex, to ensure long-term survival. (14)

Dopaminergic neurotransmission decreases during nicotine withdrawal. Programs targeting nicotine dependence that focus on DA neurotransmission alleviate withdrawal symptoms. (15) Regarding modafinil’s effects as a dopaminergic agent, it may be promising in elevating dopamine levels beyond what is expected in humans or animals experiencing withdrawal symptoms, making them vulnerable to self-administering nicotine or similar drug-seeking behaviors. Thus, users may overcome the compulsion or desire to smoke while under modafinil’s influence.

Glutamate

Glutamate release in the VTA triggers DA release, producing the rewarding effects of nicotine use. It is suggested that smoking cessation may reduce glutamate transmission, diminishing the reward elicited by nicotine use. (23) Modafinil may be promising in this regard by blocking glutamate uptake in postsynaptic neurons, thereby inhibiting the expected rewarding DA release from nicotine use. This discrepancy between expected and actual reward plays a key role in learning and relearning addictions, as well as extinction responses. By “reprogramming” the brain to no longer associate nicotine use with DA-mediated reward, modafinil may provide an effective, potentially long-term improvement in the user’s relationship with nicotine as an addictive drug.

Immediate withdrawal symptoms are a key mechanism of dependence and the abuse potential of tobacco products, particularly in smoking. Following nicotine exposure, as nicotine withdrawal effects set in, synaptic glutamate depletion occurs. This glutamate depletion and associated withdrawal symptoms are considered a primary driver of the motivation for immediate nicotine redosing. (24) Drugs that elevate synaptic glutamate levels may help alleviate nicotine withdrawal symptoms and reduce smoking cravings in abstaining smokers. (25)

Glutamate transmission plays a role in extinction learning, the process of erasing or overwriting old reward associations with new ones. (26) By creating a glutamate-rich environment, the use of modafinil may bring the brain to a stage conducive to relearning entrenched associations, such as those related to smoking addiction. Introducing compounds to increase or facilitate glutamatergic compounds has been proposed as a strategy to prevent relapse in abstaining smokers by promoting extinction and relearning. (25)

In animals, depressive symptoms during abstinence from chronic nicotine exposure have been linked to reduced glutamatergic transmission. NMDA receptor antagonists, which reduce glutamatergic transmission, may diminish nicotine’s reinforcing effects. (27) It should be noted that modafinil is considered a partial NMDA agonist, so its inhibitory effect on the glutamatergic system via NMDA receptor binding may be contradictory.

Conclusions and Suggestions for Future Research

There appear to be numerous, sometimes conflicting mechanisms by which modafinil may effectively promote nicotine abstinence during smoking cessation. Indeed, the ways in which modafinil affects a patient’s physiology are complex and far-reaching, even if highly specific in other respects. The most promising pathways for these effects seem to involve the expression of orexins or hypocretins, glutamate, and histamines, with less pronounced or specific effects on dopamine, serotonin, GABA, and MAO. Modafinil’s role as an inhibitory agent in self-administered nicotine use during smoking abstinence may be beneficial.

We propose that the most practically useful studies would be conducted over longer periods among smokers who have unsuccessfully attempted to quit and are open to using aids in smoking cessation therapy, either in combination with complete abstinence or nicotine replacement therapy in double-blind conditions, testing against a placebo control. We suggest that these smokers be monitored or report their smoking habits during their attempts to avoid smoking, allowing comparison with their prior success in quitting or reducing their habits.

Author: Joseph Parampathu

Sources:

1. https://www.ncbi.nlm.nih.gov/pubmed/10481909

2. https://www.ncbi.nlm.nih.gov/pubmed/18160631

3. http://www.sciencedaily.com/releases/2008/11/081124174851.htm

4. https://www.wpi.edu/Pubs/E-project/Available/E-project-042408-112010/unrestricted/MQP_REPORT_Zand_Angjeli.pdf

5. http://www.ncbi.nlm.nih.gov/pubmed/11014216

6. http://www.ncbi.nlm.nih.gov/pubmed/15652995

7. http://onlinelibrary.wiley.com/store/10.1111/j.1476-5381.1951.tb00620.x/asset/j.1476-5381.1951.tb00620.x.pdf;jsessionid=E0E59E09&39 49bb310f17523fe19d504dcc17754d27d127f007

8. https://www.ncbi.nlm.nih.gov/pubmed/26084539

9. http://www.ncbi.nlm.nih.gov/pubmed/12614915/

10. http://link.springer.com/article/10.1007%2Fs00011-004-1249-1

11. http://www.ncbi.nlm.nih.gov/pubmed/3317472

12. http://www.ncbi.nlm.nih.gov/pubmed/10078530

13. http://www.ncbi.nlm.nih.gov/pubmed/8774460

14. http://www.jneurosci.org/content/22/9/3306.long

15. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188825/

16. http://ajp.psychiatryonline.org/doi/full/10.1176/ajp.158.8.1341

17. http://www.gwern.net/Modafinil

18. http://www.newyorker.com/magazine/2009/04/27/brain-gain

19. http://www.ncbi.nlm.nih.gov/pubmed/6741672

20. http://www.ncbi.nlm.nih.gov/pubmed/2560221

21. http://www.ncbi.nlm.nih.gov/pubmed/16876138/

22. http://www.nature.com/npp/journal/v20/n4/full/1395268a.html

23. http://www.ncbi.nlm.nih.gov/pubmed/10900219/

24. http://www.ncbi.nlm.nih.gov/pubmed/19103434/

25. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188825/

26. http://www.ncbi.nlm.nih.gov/pubmed/20631689/

27. http://www.ncbi.nlm.nih.gov/pubmed/18418357/

28. http://www.dtic.mil/dtic/tr/fulltext/u2/p011050.pdf

29. http://www.ncbi.nlm.nih.gov/pubmed/18729534

30. http://www.ncbi.nlm.nih.gov/pubmed/17868195

31. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120247